The inflammatory response is one of the most important physiological mechanisms for the maintenance of human health. However, disorders of inflammation or an inappropriate inflammatory response can result in tissue injury, morbidity or mortality.
The cascade of biochemical processes that initiate and regulate the inflammatory response opens a variety of approaches for therapeutic intervention. However, the complexity of cellular events and physiological processes involved in acute inflammation preclude the use of a single pharmacological agent to achieve total therapeutic effectiveness.
At the cellular level the oxidative products of arachidonic acid metabolism can be thought of as members of a family of chemical substances produced in the body as part of the immunochemical response. These agents constitute a method for protection by which viruses, bacteria, or certain cells such as tumor or damaged cells are recognized and destroyed.
Upon release from cellular phospholipids, arachidonic acid is oxidatively metabolized by two principal systems, the cyclooxgenase and the 5-lipoxygenase pathways. Metabolism via the cyclooxygenase pathway sequentially generates prostaglandin endoperoxides and the corresponding endoperoxide alcohols. The biological effects of prostaglandin endoperoxides include smooth muscle contraction, complex cardiovascular effects, and rapid and irreversible platelet aggregation.
Arachidonic acid metabolism via the 5-lipoxygenase pathway produces the unstable intermediate, 5-(S)-hydroperoxy-7,9,11,14- E,Z,Z,Z!eicosatetraenoic acid 5-(S)-HPETE!. This species may be reduced to the 5-(S)-hydroxy derivative or converted to the unstable allylic epoxide leukotriene A.sub.4 (LTA.sub.4). LTA.sub.4 can be converted to the potent chemotactic agent LTB.sub.4 or to the first of a series of peptidoleukotrienes, LTC.sub.4. The peptidoleukotrienes LTC.sub.4, LTD.sub.4 and LTE.sub.4 comprise the compounds that have been termed the "slow reacting substance of anaphylaxis" and are potent broncho-constrictors and pulmonary vasoconstrictors.
Formation and release of these arachidonic acid metabolites both inter- and extracellularly mark the mobilization of bodily defenses. Further evidence of this mobilization is seen in the clinical symptoms characteristic of systemic inflammatory reaction. These include a pronounced increase in mean pulmonary artery pressure and a decrease in arterial PO.sub.2. Cardiac output and stroke volume decline while systemic vascular resistance increases. Heart rate exhibits a biphasic pattern, with an initial increase followed by a return to baseline and a subsequent elevation. Oxygen consumption increases significantly. Coincident with these cardiopulmonary events, the arterial neutrophil count declines precipitously as a consequence of pulmonary sequestration of these inflammatory cells. The release of oxygen radicals (toxic oxygen species) and proteolytic enzymes that follows this sequestration results in tissue injury marked by increased microvascular permeability to solutes and protein.
With the possible exception of clucocorticoids, there are no therapeutic agents known to be effective in preventing or ameliorating the tissue injury, such as microvascular damage, associated with acute inflammation that occurs during the early development of Adult Respiratory Distress Syndrome (ARDS). It has been discovered that attenuation of damaging components of inflammation will diminish the morbidity or mortality associated with a variety of human diseases where inflammatory processes are responsible for tissue injury.